SEARCH · PubMed Health

Results for “Benzolamide”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources

PubMed1995

The effect of temperature on the binding of sulfonamides to carbonic anhydrase isoenzymes I, II, and IV.

We report the effect of temperature on the equilibrium dissociation constants (Kl) for a series of six sulfonamides binding to three carbonic anhydrase (CA) isoenzymes (I, II, and IV). Kl values obtained at 0 degree, 15 degrees, and 23 degrees under conditions of nearly constant and low substrate (CO2) concentration were used to calculate enthalpy and entropy changes associated with sulfonamide binding as well as to provide estimates of inhibitory potency of sulfonamides at 37 degrees. We studies four classic sulfonamide (methazolamide, benzolamide, ethoxzolamide, and sulfanilamide) and the novel sulfonamides MK-507 (dorzolamide) and CF3SO2NH2. In all cases, the Kl was observed to increase with increasing temperature, which is consistent with a negative enthalpy of sulfonamide binding. The extrapolated increase in Kl over the 0-37 degrees temperature range varied from 4-fold for sulfanilamide binding to CA l to 14-fold for CF3SO2NH2 binding to CA IV, corresponding to binding enthalpy values of -7.2 to -11.7 kcal/mol. For CA II and I, entropy changes associated with sulfonamide binding were in general modest and ranged from -5.3 to +4.1 entropy units (eu) for five of the compounds tested. In contrast, ethoxzolamide binding was associated with a relatively large positive entropy change. Also, the variatione in k(on) and k(off) with temperature were studied for three sulfonamides binding to CA II. The association rate constants for methazolamide, benzolamide, and ethoxzolamide binding showed increases of 2-fold or less, whereas dissociation constants increased 3-9-fold over the range of 0-37 degrees. Thus, the temperature effect in increasing Kl is in large part due to a faster rate of sulfonamide dissociation. Apparent activation parameters at 23 degrees for k(on) were delta H++ = -2.35 to 3.8 kcal/mol, delta G++ = 7.3 to 8.6 kcal/mol, and delta S++ = -16.2 to -32.7 entropy units. For k(off), the corresponding values were delta H++ = 5.6 to 14.5 kcal/mol, delta G++ = 19.0 kcal/mol, and delta S++ = -14.8 to -45.7 entropy units.

Carbon Dioxide↗

PubMed1992

Simultaneous measurement of intracellular and extracellular carbonic anhydrase activity in intact muscle fibres.

The presence and properties of membrane-bound carbonic anhydrases have been difficult to establish with conventional enzymological and immunohistochemical techniques. We have therefore studied carbonic anhydrase (CA) activity in single intact crayfish muscle fibres by superfusing them alternately with a 4-(2-hydroxyethyl)-1-piperazine-ethanesulphonic acid (HEPES)-buffered and a 5% CO2/HCO3(-)-buffered solution (pH of both solutions 7.4) while recording the intracellular pH (pHi) and extracellular surface pH (pHs) with H(+)-selective microelectrodes. In order to prevent regulation of pHi, Na+ ions were replaced with N-methyl-D-glucamine. Application of the CO2-containing solution produced a fast fall in pHi coupled with a marked (0.5-0.8 pH units) transient increase in pHs. Submicromolar concentrations of acetazolamide (AA) and benzolamide (BA) immediately blocked the pHs transients. A concentration of 8 x 10(-8) M (both compounds) reduced the response by 50%. A more prolonged application of BA and AA at concentrations of 10(-7) M and higher slowed the CO2-induced fall in pHi, which attained a rate corresponding to uncatalysed intracellular CO2 hydration at an AA concentration of 10(-4) M. The effect of BA and AA on the pHi changes developed with a time constant of 25 +/- 4 min and 7.6 +/- 1.5 min respectively, indicating that BA is less permeant than AA. CNO- ions (5 x 10(-4) M) had little effect on the CO2-induced pHs and pHi changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetazolamide↗

PubMed2002

Inhibition of muscle carbonic anhydrase increases rise and relaxation times of twitches in rat skeletal muscle fibres.

Muscle carbonic anhydrase (CA) was inhibited in fibre bundles of the extensor digitorum longus (EDL) and soleus (SOL) muscles from rats. Isometric single twitches were recorded in the absence or presence of the CA inhibitors. The highly membrane-permeable inhibitors L-645,151, chlorzolamide (CLZ) and ethoxzolamide (ETZ) prolonged significantly the values of time-to-peak (ttp) by 5-40 ms (10-40%) in both muscles and the values of the 75% decay time (t(75%)) by 30-400 ms (13-110%) in SOL and by 9-17 ms (15-30%) in EDL and increased peak force by 20--55% in SOL and EDL. The poorly membrane-permeable inhibitors benzolamide (BZ) and acetazolamide (ACTZ) had no effects on single twitches. In CO(2)-free solution, the effects of L-645,151 on ttp, t(75%) and peak force of SOL were reduced drastically. Removal of CO(2) prolonged ttp and t(75%). In skinned fibres, ETZ and CLZ did not increase force production. Intracellular pH (pH(i)) in SOL and EDL fibres was not affected by 30-60 min exposure to CLZ, ETZ or BZ. The results of L-645,151, CLZ and ETZ on ttp, t(75%) and peak force of twitches are consistent with our hypothesis on the role of the sarcoplasmic reticulum (SR) CA. The SR-CA may mediate sufficiently fast buffering and production of H(+) in the SR that is exchanged for Ca(2+) across the SR membrane. We propose that a H(+) buffering and delivery impaired by CA inhibition slows the kinetics of Ca(2+) release and reuptake and, as a result, slows twitch ttp and t(75%). Aspects of this hypothesis await further validation.

Acetazolamide↗

PubMed2004

Effect of carbonic anhydrase inhibition on GFR and renal hemodynamics in adenosine-1 receptor-deficient mice.

The reduction of glomerular filtration rate (GFR) caused by inhibitors of carbonic anhydrase (CA) is thought to be initiated by activation of the tubuloglomerular feedback (TGF) mechanism. We determined the effect of the CA inhibitor benzolamide (Bz) on renal hemodynamics in adenosine-1 receptor (A1AR) knockout mice that have been shown previously to lack a TGF response. In A1AR(+/+) mice, Bz (150 microg plus 2 microg/min) reduced RBF by 19.8% (from 829+/-42 to 666+/-44 microl/min; n=7), and GFR by 19.8% (from 396+/-43 to 324+/-46 microl/min; n=9, P=0.001). In A1AR(-/-) mice, RBF fell by 15.9 % (from 809+/-24 to 680+/-40 microl/min; n=7), and GFR by 21.1% (from 358+/-27 to 287+/-32 microl/min; n=10, P=0.0003; NS compared with A1AR(+/+)). The absence of TGF responses both before and during Bz infusion in A1AR(-/-) mice was confirmed by micropuncture. Following angiotensin II-receptor blockade with candesartan, Bz did not alter RBF (1.4+/-0.2 vs. 1.4+/-0.15 ml/min in A1AR(+/+), and 1.4+/-0.22 vs. 1.39+/-0.2 ml/min in A1AR(-/-); n=5/genotype) while GFR changed by -8.9 % in A1AR(+/+) mice ( n=7), and by -1% in A1AR(-/-) mice ( n=9; NS compared with A1AR(+/+)). Bz caused a significant rise of plasma renin concentration in both A1AR(+/+) and A1AR(-/-) mice. Our data show that the absence of a functional TGF mechanism does not prevent the reduction in GFR or RBF caused by CA inhibition. Acute angiotensin II receptor blockade, on the other hand, diminishes the effect of CA inhibition on GFR and RBF. The causes for the GFR reduction appear to be complex and include an effect of the renin-angiotensin system.

Angiotensin II Type 1 Receptor Blockers↗

PubMed1991

Renal carbonic anhydrase inhibition reduces high altitude sleep periodic breathing.

The efficacy of carbonic anhydrase (CA) inhibitors in amelioration of periodic breathing during sleep at high altitude is not fully understood. Although CA is present in a number of tissues, we hypothesized that selective renal CA inhibition without physiologically important inhibition of other tissue CA, may be sufficient alone by its generation of a mild metabolic acidosis to stimulate ventilation and prevent periodic breathing. We studied benzolamide (3 mg/kg), a selective inhibitor of renal CA, in 4 climbers on ventilation and ventilatory responses at sea level and on arterial O2 saturation (SaO2%) and periodic breathing during sleep at altitude. At sea level, ventilation increased and PaO2 rose accompanied by a mild metabolic acidosis. The isocapnic hypoxic ventilatory response was unchanged but the hyperoxic hypercapnic ventilatory response rose 40%. At high altitude (4400 m), daytime SaO2% improved from 81 to 85 and venous plasma HCO3- fell from 18.9 to 14.8 mM. During sleep, mean SaO2% rose from 76 to 80 and periodic breathing decreased 75%. We conclude that metabolic acidosis occurring with all CA inhibitors is one of the major stimulant actions of these drugs on ventilation while awake and during sleep at high altitude.

Acidosis↗

PubMed2003

Carbonic anhydrase inhibitors: topically acting antiglaucoma sulfonamides incorporating esters and amides of 3- and 4-carboxybenzolamide.

Reaction of 3- and 4-carboxybenzenesulfonyl chloride with 5-amino-1,3,4-thiadiazole-2-sulfonamide/5-imino-4-methyl-delta(2)-1,3,4-thiadiazoline-2-sulfonamide afforded two series of benzolamide analogues to which the carboxyl moiety has been derivatized as esters or amides, in order to reduce their very polar character. The new derivatives showed low nanomolar affinity for three carbonic anhydrase (CA) isozymes, CA I, II and IV, and were effective as topical antiglaucoma agents in normotensive rabbits. Efficacy of several of the new sulfonamides reported was better than that of the standard drugs dorzolamide and brinzolamide, whereas their duration of action was prolonged as compared to that of the clinically used drugs.

Administration, Topical↗

PubMed1976

Potassium secretion by the decending limb or pars recta of the juxtamedullary nephron in vivo.

Potassium reabsorption by the juxtamedullary nephron up to the hairpin turn was studied by the micropuncture technique in the exposed renal papilla of rats. In 18 nondiuretic rats, the fraction of filtered potassium remaining at the end of the desdending limb averaged 113 +/- 9%, indicating either that potassium is not reabsorbed by the juxtamedullary proximal tubule and descending limb or that potassium is reabsorbed and secreted in those segments. Furosemide, a drug which inhibits NaCl reabsorption in the ascending limb downstream from the descending limb, significantly decreased the potassium remaining at the end of the descending limb from 106 +/- 12 to 72 +/-11% in seven rats. Benzolamide, a drug which inhibits reabsorption of NaHCO3 and water in the proximal tubule upstream from the descending limb significantly increased the potassium remaining from 103 +/- 13 to 177 +/- 32% in eight rats. These findings support the hypothesis that in the rat, potassium is normally reabsorbed by the proximal convoluted tubule and secreted in the pars recta or descending limb of the juxtamedullary nephron.

Absorption↗

PubMed1976

Effect of intraluminal bicarbonate and chloride on fluid absorption by the rat renal proximal tubule.

In order to study mechanisms of fluid transport in the rat renal proximal convoluted tubule, the effects of large variations in intraluminal HCO3- and Cl- concentrations were measured by microperfusion techniques. No differences in rates of fluid transport were found when intraluminal HCO3- was varied from 4 to 30 mEq/liter and Cl- from 146 to 120 mEq/liter. Inhibition of H+ secretion with benzolamide had no effect on fluid absorption when little or no HCO3- was present in the lumen, but did reduce fluid transport when 25 mEq of HCO3- was present. If several different mechanisms are responsible for proximal fluid transport, such as nonelectrogenic active NaHCO3 transport, passive chloride diffusion and active sodium transport linked to H+ secretion, the above observations imply that they all operate at approximately the same rate, since the dominant driving force would have been different with each perfusion solution. The data seem more compatible with the view that active sodium transport is the major driving force for fluid absorption in the proximal tubule, that this is not linked to H+ secretion and that anions modify the rate of absorption only to the degree that they are able to accompany sodium across the epithelium. An additional observation was that absorption of isotonic NaCl was very slow in short segments of tubule, as compared to HCO3--containing perfusion solutions. Although the mechanism is uncertain, these data suggest that a finite amount of intraluminal HCO3- is necessary for optimal proximal fluid transport.

Animals↗

PubMed1988

The effects of topical and general anesthesia on ocular drug levels and intraocular pressure lowering activity of topically applied carbonic anhydrase inhibitors.

Treatment with topical anesthetics was reported to increase corneal permeability and improve ocular drug bioavailability. These changes were attributed to the loss of reflex blinking, reduction of tear secretion and appearance of superficial corneal epithelial lesions. A recent report showed that pretreatment with Ophthetic (0.5% proparacaine HCl) (OPH) in pentobarbital-anesthetized rabbits significantly increased the permeability of the lipophobic carbonic anhydrase inhibitor (CAI) benzolamide (B) and transformed it to a highly active ocular hypotensive drug. This did not affect the permeability and activity of other, more lipophilic, CAI like methazolamide and ethoxzolamide (E). Similar experiments in awake rabbits using other CAI failed to reproduce the finding reported for B. We compared the ocular drug levels and the intraocular pressure lowering (delta IOP) with and without application of Ophthetic prior to 1 drop of 2% suspensions, in groups of anesthetized and conscious albino rabbits. In unanesthetized rabbits pretreatment with Ophthetic, lidocaine or benzalkonium had minimal and insignificant effects on ocular drug levels and delta IOP of B as well as E. On the other hand, Ophthetic or lidocaine pretreatment in anesthetized rabbits led to a highly significant increase in both ocular drug levels and hypotensive activity of B. We conclude that the error introduced by pretreatment with OPH occurs only in the presence of pentobarbital anesthesia and has little relevance to the normal, unanesthetized condition.

Administration, Topical↗

PubMed2001

Extracellular carbonic anhydrase activity facilitates lactic acid transport in rat skeletal muscle fibres.

1. In skeletal muscle an extracellular sarcolemmal carbonic anhydrase (CA) has been demonstrated. We speculate that this CA accelerates the interstitial CO2/HCO3- buffer system so that H+ ions can be rapidly delivered or buffered in the interstitial fluid. Because > 80 % of the lactate which crosses the sarcolemmal membrane is transported by the H+-lactate cotransporter, we examined the contributions of extracellular and intracellular CA to lactic acid transport, using ion-selective microelectrodes for measurements of intracellular pH (pHi) and fibre surface pH (pHs) in rat extensor digitorum longus (EDL) and soleus fibres. 2. Muscle fibres were exposed to 20 mM sodium lactate in the absence and presence of the CA inhibitors benzolamide (BZ), acetazolamide (AZ), chlorzolamide (CZ) and ethoxzolamide (EZ). The initial slopes (dpHs/dt, dpHi/dt) and the amplitudes (DeltapHs, DeltapHi) of pH changes were quantified. From dpHi/dt, DeltapHi and the total buffer factor (BFtot) the lactate fluxes (mM min-1) and intracellular lactate concentrations ([lactate]i) were estimated. 3. BFtot was obtained as the sum of the non-HCO3- buffer factor (BFnon-HCO3) and the HCO3- buffer factor (BFHCO3). BFnon-HCO3 was 35 +/- 4 mM pH-1 for the EDL (n = 14) and 86 /- 16 mM pH-1 for the soleus (n = 14). 4. In soleus, 10 mM cinnamate inhibited lactate influx by 44 % and efflux by 30 %; in EDL, it inhibited lactate influx by 37 % and efflux by 20 %. Cinnamate decreased [lactate]i, in soleus by 36 % and in EDL by 45 %. In soleus, 1 mM DIDS reduced lactate influx by 18 % and efflux by 16 %. In EDL, DIDS lowered the influx by 27 % but had almost no effect on efflux. DIDS reduced [lactate]i by 20 % in soleus and by 26 % in EDL. 5. BZ (0.01 mM) and AZ (0.1 mM), which inhibit only the extracellular sarcolemmal CA, led to a significant increase in dpHs/dt and pHs by about 40 %-150 % in soleus and EDL. BZ and AZ inhibited the influx and efflux of lactate by 25 %-50 % and reduced [lactate]i by about 40 %. The membrane-permeable CA inhibitors CZ (0.5 mM) and EZ (0.1 mM), which inhibit the extracellular as well as the intracellular CAs, exerted no greater effects than the poorly permeable inhibitors BZ and AZ did. 6. In soleus, 10 mM cinnamate inhibited the lactate influx by 47 %. Addition of 0.01 mM BZ led to a further inhibition by only 10 %. BZ alone reduced the influx by 37 %. 7. BZ (0.01 mM) had no influence on the Km value of the lactate transport, but led to a decrease in maximal transport rate (Vmax). In EDL, BZ reduced Vmax by 50 % and in soleus by about 25 %. 8. We conclude that the extracellular sarcolemmal CA plays an important role in lactic acid transport, while internal CA has no effect, a difference most likely attributable to the high internal vs. low extracellular BF(non-HCO3). The fact that the effects of cinnamate and BZ are not additive indicates that the two inhibitors act at distinct sites on the same transport pathway for lactic acid.

Animals↗

PubMed2004

Temporal adaptation of tubuloglomerular feedback: effects of COX-2.

BACKGROUND: Reductions in proximal reabsorption cause increases in delivery of sodium chloride to the macula densa (MD), which activates the tubuloglomerular feedback (TGF) mechanism and reduces glomerular filtration rate. TGF undergoes temporal adaptation, permitting filtration rate to rise in spite of elevated MD delivery of NaCl. Inhibitors of nitric oxide synthase I (NOS I) prevent TGF adaptation, but angiotensin-converting enzyme inhibitors have no effect. COX-2 activity moves in parallel with changes in NOS I and intrarenal renin. We examined the impact of COX-2 inhibition on TGF temporal adaptation and effects of inhibition of COX-2 and NOS I on plasma and kidney angiotensin II (Ang II). METHODS: Kidney blood flow (RBF) and glomerular filtration rate (GFR) were measured before and during benzolamide (BNZ) infusion in control Wistar rats and rats concurrently receiving COX-2 inhibitors. Plasma and kidney angiotensin II content was evaluated by radioimmunoassay in control rats, rats after 60 minutes of BNZ, and during COX-2 and NOS-1 inhibition after BNZ. RESULTS: BNZ reduced both RBF and GFR in all groups. During BNZ, RBF and GFR returned to normal control values within 60 minutes. COX-2 inhibitors totally prevented TGF adaptation. Plasma and kidney Ang II did not change after BNZ, and NOS I and COX-2 inhibitors had no effect on plasma or intrarenal Ang II. CONCLUSION: Within 1 hour after BNZ, rats undergo TGF temporal adaptation. Administration of COX-2 inhibitors prevented TGF temporal adaptation, identical to the effect of NOS I inhibition. Changes in intrarenal Ang II cannot explain this prevention of TGF temporal adaptation.

Adaptation, Physiological↗

PubMed1975

Transmembrane exchange of chloride with bicarbonate ion in mammalian red blood cells: evidence for a sulphonamide-sensitive "carrier".

1. It is well known that red blood cells suspended in isotonic NH4Cl solution swell because penetration of NH3 induces a transmembrane exchange between Cl-o and OH-i(or HCO3-i). The rate of swelling thus depends on the speed of the transmembrane exchanges and on the amount of anions available for exchange. 2. It has been demonstrated in experiments carried out in a CO2-free medium that OH-ions are poorly permeating whereas the permeability for HCO3-is very high. Thus the rate of swelling is largely dependent on the intracellular HCO3-concentration. In this context the well-known inhibitory effect of sulphonamides upon swelling can be interpreted, and always has been until now, as being due to the inhibitory action of the drug on the intracellular carbonic anhydrase. However, this inhibitory effect could also result from a direct action of the drug on the transmembrane exchange; it would explain why under conditions of total carbonic anhydrase inhibition we have shown that the inhibition of swelling is far from maximal. 3. A direct experimental evidence of such an effect of carbonic anhydrase inhibitors on the transmembrane exchange of Cl-with HCO3- was obtained with benzolamide (Cl 11,366), Cl 13,580 and ethoxzolamide. Surprisingly enough, however, acetazolamide (Diamox) does not affect the transmembrane exchange process. 4. The inhibitory effect of sulphonamides on HCO3-transport process is discussed in terms of an interaction of the drug with a transport system common to HCO3- and organic anions.

Acetazolamide↗

PubMed1984

Association between HCO3(-) absorption and K+ uptake by Amphiuma jejunum: relations among HCO3(-) absorption, luminal K+, and intracellular K+ activity.

Titration techniques and K+- sensitive microelectrodes have been used to investigate the relations among HCO3(-) absorption, luminal K+, and intracellular K+ activity in in vitro Amphiuma jejunum. The HCO3(-) absorptive flux (JHCO3(-] measured by pH-stat under short circuit was reduced by removal of K+ from the medium but not by replacement of Na+ with choline. JHCO3(-) exhibited a seasonal variation when K+ was absent from the media and was increased to a maximum when K+ equaled 5 mM. Addition of K+ to a K+-free luminal medium stimulated JHCO3(-) much more than addition to the serosal medium. Acetazolamide (10(-4) M) blocked K+-stimulated HCO3(-) absorption while benzolamide reduced the short-circuit current associated with HCO3(-) absorption much more rapidly when added to the mucosal bathing medium. Intracellular K+ activity (aik) and mucosal membrane potential (psi m) of jejunal villus cells were measured with double-barreled microelectrodes. When bathed bilaterally with HCO3(-)-containing media, K+ was actively accumulated for many hours (aik = 58.5 mM) but in the presence of ouabain fell to equilibrium (16 mM) after 2 h. In contrast, when HCO3(-) absorption was induced by removal of serosal HCO3(-), aik was elevated to 83.6 mM and, after 4-h exposure to ouabain cell K+, remained far above electrochemical equilibrium at 33 mM. Tissues bathed in Na+-free (Tris) media containing ouabain retained cell K+ after 4 h at even higher levels (46 mM). Cell K+ activity was reduced by removal of K+ from either the mucosal or serosal medium. Acetazolamide reduced aik over 2 h in Na+-free media from 66 to 42 mM. The decline in aik was associated with a concomitant decline in the HCO3(-) absorptive current. It is concluded that K+ is actively accumulated across both luminal and serosal membranes of the jejunal absorptive cell and that the luminal uptake mechanism is linked to HCO3(-) absorption or an equivalent process.

Absorption↗

PubMed2000

Acid-base effects on electrolyte transport in CA II-deficient mouse colon.

To determine the role of carbonic anhydrase (CA) in colonic electrolyte transport, we studied Car-2(0) mice, mutants deficient in cytosolic CA II. Ion fluxes were measured under short-circuit conditions in an Ussing chamber. CA was analyzed by assay and Western blots. In Car-2(0) mouse colonic mucosa, total CA activity was reduced 80% and cytosolic CA I and membrane-bound CA IV activities were not increased. Western blots confirmed the absence of CA II in Car-2(0) mice. Normal mouse distal colon exhibited net Na(+) and Cl(-) absorption, a serosa-positive PD, and was specifically sensitive to pH. Decrease in pH stimulated active Na(+) and Cl(-) absorption whether it was caused by increasing solution PCO(2), reducing HCO(-)(3) concentration, or reducing pH in CO(2)/HCO(-)(3)-free HEPES-Ringer solution. Membrane-permeant methazolamide, but not impermeant benzolamide, at 0.1 mM prevented the effects of pH. Car-2(0) mice exhibited similar basal transport rates and responses to pH and CA inhibitors. We conclude that basal and pH-stimulated colonic electrolyte absorption in mice requires CA I. CA II and IV may have accessory roles.

Acid-Base Equilibrium↗

PubMed1976

Early postglomerular plasma concentrations of chloride, sodium, and inulin in the rat kidney.

Sodium, chloride, and inulin concentrations were measured in plasma collected from the terminal portions of long efferent vessels at the subcapsular surface of the rat kidney. Sodium concentration equaled and the concentrations of chloride and inulin were less than those in peripheral plasma. During benzolamide infusion, chloride concentration equaled while inulin concentration remained less than in peripheral plasma. In free-flow micropuncture samples collected randomly during control conditions, chloride concentration rose rapidly in the early proximal tubule and then remained elevated and constant throughout the remainder of the proximal tubule accessible to micropuncture. These experiments indicate that normally tubular reabsorbate low in chloride and inulin is added to the blood traversing the early postglomerular vessels before reaching the kidney surface. Bases on the analyses of proximal tubular fluid, this type of reabsorbate appears available only from the early proximal tubular segment. We conclude that a close functional relationship exists between the first segment of the proximal tubule and the early postglomerular blood supply characteristic of the superficial cortical nephron.

Animals↗

PubMed2007

Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition.

Hypoxic pulmonary vasoconstriction (HPV) occurs with ascent to high altitude and can contribute to development of high altitude pulmonary edema (HAPE). Vascular smooth muscle contains carbonic anhydrase (CA), and acetazolamide (AZ), a CA inhibitor, blunts HPV and might be useful in the prevention of HAPE. The mechanism by which AZ impairs HPV is uncertain. Originally developed as a diuretic, AZ also has direct effects on systemic vascular smooth muscle, including modulation of pH and membrane potential; however, the effect of AZ on pulmonary arterial smooth muscle cells (PASMCs) is unknown. Since HPV requires Ca2+ influx into PASMCs and can be modulated by pH, we hypothesized that AZ alters hypoxia-induced changes in PASMC intracellular pH (pH(i)) or Ca2+ concentration ([Ca2+](i)). Using fluorescent microscopy, we tested the effect of AZ as well as two other potent CA inhibitors, benzolamide and ethoxzolamide, which exhibit low and high membrane permeability, respectively, on hypoxia-induced responses in PASMCs. Hypoxia caused a significant increase in [Ca2+](i) but no change in pH(i). All three CA inhibitors slightly decreased basal pH(i), but only AZ caused a concentration-dependent decrease in the [Ca2+](i) response to hypoxia. AZ had no effect on the KCl-induced increase in [Ca2+](i) or membrane potential. N-methyl-AZ, a synthesized compound lacking the unsubstituted sulfonamide group required for CA inhibition, had no effect on pH(i) but inhibited hypoxia-induced Ca2+ responses. These results suggest that AZ attenuates HPV by selectively inhibiting hypoxia-induced Ca2+ responses via a mechanism independent of CA inhibition, changes in pH(i), or membrane potential.

Acetazolamide↗

PubMed1992

Luminal pH in the amphibian distal tubule: effects of carbonic anhydrase and carbonic anhydrase inhibitors.

To better delineate acid-base transport properties in the distal tubule (DT) of Necturus in vivo, we 1) studied the effects of peritubular (pt) isohydric increase of PCO2 and [HCO3-]pt on luminal pH (pHlu), and 2) measured the steady-state pHlu under various experimental conditions. The experiments were carried out on initial (DTi) or distal (DTd) loops of the DT in control state and then during intravenous infusion of carbonic anhydrase (CA) or CA inhibitors (CAI). In control state, isohydric increase of PCO2 and [HCO3-]pt results in transient acidification of the DTi lumen, whereas in DTd lumen the same maneuver yields sustained (plateau) acidification. Under systemic infusion of CAI, isohydric increase of PCO2 and [HCO3-]pt lowers pHlu (sustained fall of pHlu) in DTi and DTd, whereas under CA infusion both segments exhibit only transient acidification. During intravenous infusion with benzolamide DTi steady-state pHlu falls, suggesting that this maneuver inhibits a functional luminal CA, in contrast to the DTd, whose pHlu remains unaltered. Intravenous infusion of CA significantly increases steady-state DTd pHlu; by contrast, steady-state pHlu in DTi does not change. These data are consistent with the presence of functional luminal CA in the DTi, whereas the DTd segment lacks the luminal enzyme.

Acetazolamide↗

PubMed1997

Reduced proximal reabsorption resets tubuloglomerular feedback in euvolemic rats.

Inhibition of renal carbonic anhydrase reduces proximal reabsorption and activates tubuloglomerular feedback (TGF). The TGF response is saturable, with highest gain focused near the natural flow rate. Therefore, any large change imposed on ambient tubular flow should reduce the TGF response to subequent flow perturbations. However, TGF tends to align with ambient flow regardless of the rate of ambient flow, suggesting that TGF resets to accommodate changes in flow while maintaining feedback efficiency. We used micropuncture and videometric flow velocitometry to test for TGF resetting in free-flowing nephrons during systemic infusion of the carbonic anhydrase inhibitor benzolamide (BNZ, 5 mg x kg(-1) x h(-1)) in euvolemic rats. Late proximal flow (V(LP)) and the fractional compensation (C) of TGF for perturbations in V(LP) were assessed repeatedly before and during BNZ. Early on, BNZ reduced C, consistent with TGF saturation. Over the next 45-60 min, V(LP) increased gradually by approximately 5 nl/min as C recovered to pre-BNZ levels. BNZ also increased V(LP) by approximately 5 nl/min when TGF was rendered inoperative by intratubular wax block, but this increase occurred rapidly. These data demonstrate rightward resetting of TGF during reduced proximal reabsorption.

Absorption↗